Use of a growth factor in a slimming composition

ABSTRACT

Utilization of a growth factor as active principle of a slimming and lipolytic composition and its utilization in a treatment method particularly in the process for improving the aesthetic aspect of the skin. The slimming composition may also contain the growth factor in association with a lipolytic substance such as caffine.

The subject of the present invention is the use of a growth factor asthe active principle in the preparation of a slimming and lipolyticcomposition and its application in a method of treatment for improvingthe aesthetic appearance of the skin. The present invention is alsodirected to a slimming composition containing a growth factor combinedwith another lipolytic substance such as caffeine.

BACKGROUND OF THE INVENTION

Growth factors are polypeptide molecules shown by in vivo and in vitrostudies to multiply and differentiate cells of different origins andspecies. For some of these growth factors, it has been possible todetermine the amino acid sequence and the structure of the correspondinggene. Among tissue growth factors, which were studied in depth becauseof the multiplicity of the target cells concerned, or the biologicaleffects observed, and because of the therapeutic impact that physiciansand particularly dermatologists may expect, it should be mentioned inparticular, Epidermal Growth Factor (EGF), Fibroblast Growth Factor(FGF) and Eye Derived Growth Factor (EDGF).

The expression "growth factor" is also understood to mean mixtures ofgrowth factors, particularly that derived from nerve tissue, hereinaftercalled m-NTGF (mixture of Nervous Tissue Growth Factors) as well asother peptides or polypeptides with a growth factor character of naturalor synthetic origin.

Growth factors have a stimulating effect on cell proliferation,particularly that of epithelial cells, and have proved effective in thescarring of lesions.

Some of these growth factors are used in cosmetology for skin care asdescribed for example in French Patent Application No. 79.31731(Publication No. 2.472.385) and particularly in its Certificate ofAddition No. 82.15559 (Publication No. 2.533,438). However, in thesereferences their mitogenic activity is assumed to render these factorsuseful in skin care.

The studies on EGF that may be mentioned in particular are the articlesby G. Carpenter et al., Ann. Rev. Biochem., 48, 193-216 (1979) and L. E.King et al., Progress in Dermatology, Vol. 19, No. 1, 1-8 (1985).

Among the studies on FGF, particular mention may be made of the articlesby D. Gospodarowicz et al., J. Cell, Physiol. Supp., 5/15-26 (1987), andGary D. Shipley, et al., J. Cell. Physiol. 138/511-518 (1989).

Among the articles on EDGF, reference may be made to the articles by D.Barritault, et al., Journal of Neuroscience Research, 8:477-490 (1982)and A. Y. Fourtanier, et al., The Journal of Investigative Dermatology,Vol. 87, No. 1, 76-80 (1986).

It has now been discovered quite unexpectedly that these growth factorshave a lipolytic effect and can be used as active principles in slimmingcompositions.

It has been found in particular that these growth factors may be used tocombat cellulitis and local fat overload.

It is known that swelling of the subcutaneous connective tissue, knownas cellulitis, gives the skin an "upholstered" appearance. Cellulitis isformed by local accumulation of fat and water trapped in a matrix ofmore or less fluid-tight compartments.

BRIEF DESCRIPTION OF THE DRAWINGS

Topical application of an anticellulitic agent may erase localaccumulation of fat by lipolytic action. The best-known and mostwidespread method of stimulating lipolysis is by inhibitingphosphodiesterase to prevent or at least limit the rate of cyclic AMPbreakdown. Phosphodiesterase destroys cyclic AMP converting it into 5'AMP so that it is unable to activate lipolysis. Hence the point is toinhibit the action of phosphodiesterase to achieve a high level ofcyclic AMP in the adipocytes in order to stimulate lipolytic activity.

Among the various phosphodiesterase inhibitors recommended as slimmingagents, xanthine bases, particularly caffeine, may be mentioned inparticular. However, caffeine, particularly at high concentrations, isnot always tolerated, even topically, because it penetrates and may giverise to palpitations in certain particularly sensitive subjects. It hasnow been quite unexpectedly discovered that growth factors are excellentsubstitutes or supplements for caffeine. Thus, without limiting thescope of the invention, it is assumed that growth factors owe theirlipolytic effect to an action mechanism different from that of caffeine.

SUMMARY OF THE INVENTION

A primary object of the present invention is the use of a growth factorin the preparation of a slimming composition for topical or oraladministration. These compositions may contain growth factors alone orin combination with other lipolytic agents such as for examplexanthines, particularly caffeine, or alpha-tocopherol nicotinate, colaextract, carnitine, and vitamin E and its acetate. Thus, in the case ofcaffeine-based compositions, utilization of which may cause problems, itis possible to introduce a growth factor and reduce the necessary doseof caffeine while retaining a good lipolytic effect.

A further object of the present invention is a slimming compositioncharacterized by containing in combination at least one growth factorand another lipolytic substance, preferably caffeine.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows the results of this study as a function of the quantity ofradioactivity found in the fatty acids released by lipolysis.

Among the growth factors that can be used according to the presentinvention, all the above-listed growth factors can be cited. Preferably,a mixture of factors such as m-NTGF can be used.

The m-NTGF factors are obtained from whole brains or brain fractions, ofvarious origins, after enzymatic or physical-chemical hydrolysis andmolecular screening to collect the fragments with molecular weightscorresponding to those of growth factors.

Other slimming substances may also be used according to the invention.Oily water-soluble or water-alcohol plant extracts may be cited.

Among the oily plant extracts, the following extracts may be cited:

Climbing ivy (Hedera helix) extract obtained, for example, by prolongedsoaking of the leaves in propylene glycol;

Arnica (Arnica montana L) extract obtained, for example, by soaking thecapitula of the arnica flowers in glycol or apricot oil;

Rosemary (Rosmarinus officinalis N) extract obtained, for example, byprolonged soaking of the leaves in glycol or apricot oil;

Marigold (Calendula officinalis) extract obtained, for example, byprolonged soaking of the flowers in glycol or apricot oil;

Sage (Salvia officinalis L) extract obtained, for example, by prolongedsoaking of the leaves in glycol or apricot oil;

Ginseng (Panax ginseng) extract obtained, for example, by soaking theginseng roots in a neutral oil;

St.-John's-wort (Hypericum perforatum) extract obtained, for example,from the flowers by soaking in a neutral oil or glycol;

Butcher's-broom extract obtained, for example, from butcher's-broom(Ruscus aculeatus L) rhizomes ground and extracted in a water-alcoholsolution of an alcohol having 3 to 6 carbon atoms, preferablywater-saturated n-butanol;

Meadowsweet (Filipendula ulmaria L) extract obtained, for example, byprolonged soaking of the whole plant in a neutral oil or in isopropylmyristate;

Orthosiphon (Orthosiphon stamincus Benth) extract obtained, for example,by prolonged soaking of the floral capitula in a neutral oil;

Alga (Fucus vesiculosus) extract obtained, for example, by prolongedsoaking of the whole plants in an oxyethylenated oil.

Among the water-soluble extracts, the following extracts may be cited:

Water-soluble algae extract, water-glycol extract obtained, for example,by prolonged soaking of Fucus vesiculosus thalli;

The water-soluble extract of climbing ivy (Hedera helix), a water-glycolextract obtained, for example, by prolonged soaking of the leaves andstems;

The water-soluble extract of birch (Betula alba), a water-glycol extractobtained, for example, by prolonged soaking of the bark.

Among the water-alcohol extracts, the following extract may be cited:

The water-alcohol extract of the cola nut (Cola nipida) obtained, forexample, by leaching the seeds in alcohol.

According to the invention, the growth factor is generally present in aconcentration of between 0.01 and 25% by weight, preferably between 0.5and 10 wt. % relative to the total weight of the composition.

When these compositions are administered topically, they may be invarious forms, particularly in the anhydrous form such as an oil orointment, or in the form of an O/W or W/O emulsion with the appearanceof a cream or milk, or in the form of a gel and also in the form oflipid vesicles made of ionic lipids (liposomes) or nonionic lipids.

When the compositions according to the invention are administeredorally, they may be in the form of tablets, capsules, coated pills,syrups, suspensions or solutions.

When the composition is in the anhydrous form, the excipient may be avegetable or animal oil, a mineral oil, a synthetic oil, or mixtures ofthese oils.

Among the vegetable or animal oils, modified or unmodified, thefollowing may be cited as examples: sweet almond oil, avocado oil, oliveoil, jojoba oil, perhydrosqualene, calophyllum oil, lanolin and itsderivatives, sunflower oil, wheat-germ oil, sesame oil, peanut oil,grapeseed oil, soy oil, rapeseed oil, safflower oil, coconut oil, cornoil, hazelnut oil, karite butter, Shorea robusta oil, palm oil andapricot oil.

Among the mineral oils, Vaseline oil may be employed, and among thesynthetic oils: ethyl and isopropyl palmitates, alkyl myristates such asisopropyl, butyl, and cetyl myristate, hexyl stearate, octanoic anddecanoic acid triglycerides (for example the product sold under the name"Miglyol" by the Dynamit Nobel Company), cetyl ricinoleate, stearyloctanoate (purcelin oil), and hydrogenated polyisobutene as well aswaxes such as ozokerite may be used.

The fatty excipient can also contain certain compounds considered asfats such as long-chain alcohols such as cetyl alcohol, stearyl alcohol,myristic alcohol, hydroxystearyl alcohol, oleic alcohol, and isostearylalcohol.

When the compositions are in the form of an emulsion, the fatty phase ofthe emulsion represents 10 to 80 wt. %, the water phase 15 to 80%, andthe emulsifier 5 to 30 wt. % relative to the total weight of theemulsion.

When the compositions are in the form of vesicles, the active principle,when it is fat-soluble, is encapsulated in the lipid lamellar phase andin the aqueous phase when the active principle is water-soluble.

The compositions according to the invention can also contain variousconventional ingredients such as for example surfactants, emollients,thickeners, polymers, silicone oils, fragrances, dyes, sweeteners,antioxidants, or preservatives.

Among the silicone oils, cyclopentadimethylsiloxane, particularly theproduct sold under the name "Volatile Silicone 7158" by the UnionCarbide Company as well as alkyldimethicone copolyol, particularly theproduct sold under the name "Abil We 09" by the Goldschmidt Company, arepreferably used.

The surfactants preferably used are glycerin monostearate, particularlythe product sold under the name "Arlacel 165" by the Atlas Company, aswell as sorbitan monostearate oxyethylenated (OE) with the aid of 20moles of OE, particularly the product sold as "Tween 60" by the AtlasCompany, or a surfactant mixture sold under the commercial name"Protegin X" by the Goldschmidt Company.

The emollients preferably used are polymers of ethylene oxide, glycerolcocoate oxyethylenated with 7 moles of OE, particularly the product soldunder the name "Cetiol HE" by the Henkel Company as well as the mixtureof glycol stearate and polyethylene glycol (PEG 6 and 32), particularlythe product sold under the name "Tefose 63" by the Gattefosse Company.

The thickeners preferably used are silica derivatives such aspyrogenated colloidal silica, particularly the product sold under thename "Aerosil 200" by the Degussa AG Company as well as crosslinkedpolyacrylic acid, particularly the products sold under the names"Carbopol 940" and "Carbopol 941" by the Goodrich Company.

A still further object of the present invention is a treatment methoddesigned to combat cellulitis and local fat overload and to improve theaesthetic appearance of a person, characterized by application to theskin or oral administration of a composition containing at least onegrowth factor as the lipolytic active principle.

The treatment method according to the invention is generally conductedover a period of 1 to 35 weeks with 1 to 3 applications oradministrations per day. In the case of oral administration, the dosagemay be for example 1 to 10 (400 mg) capsules (containing 100 mg ofactive principle each) per day depending on the body weight of theperson to be treated.

Study of Lipolytic Effect

The techniques of incorporating the C¹⁴ -labeled lipid precursors suchas sodium acetate allow the kinetics of lipid production and release bythe cells producing them to be monitored and the influence of variousfactors or active substances to be studied. The lipids produced by thesecells are radiolabelled by providing such precursors to lipid-producingcells. The same cells, whose lipids are radiolabelled, can then besubjected to lipolysis by the action of a lipolytic agent that releasesthe quantifiable radioactive elements.

In order to demonstrate the lipolytic activity of the growth factorsused according to the present invention, a mixture of growth factorsfrom the pituitary gland was taken and its lipolytic activity comparedin vitro to that obtained by caffeine as a known lipolytic substance.

The study of the lipolytic effect of these active substances wasperformed on cultured fat cells which, contrary to adipocytes isolatedfrom fatty tissue which cease to be viable after a few hours, can bestored for up to three weeks with no loss of viability (Alihaud G., Mol.Cell. Biochem. 49 (1982) 17-31). Differentiated rat Ob 17 cells culturedunder specific conditions were used (Gaillard D. et al. Biochim.Biophys. Acta, 846 185-91 (1985) and Doglio A. et al. Biochem. J. 238123-129 (1986) ).

The lipolysis experiments were conducted after exposure of the cells toC¹⁴ -labeled acetate (two periods of 48 hours in the presence of 0.5μCi/dish). Under steady-state conditions, the radioactivity was foundprincipally in the triglyceride fatty acids (Negrel R. et al. Proc.Natl. Acad. Sci. USA, 75 6054-6058 (1978), and Forest C. et al. Exp.Cell. Res. 168 218-232 (1987)).

The lipolysis tests were conducted at 37° C. as a function of time withtwo dishes per concentration and a minimum of four kinetic points perdish.

Thus each substance was studied for dose-response (six concentrationsper active substance at the various powers of ten between 10⁸ and 10³M).

FIG. 1 shows the results of this study as a function of the quantity ofradioactivity found in the fatty acids released by lipolysis. In FIG. 1,the maximum value of 100 arbitrary units corresponds to isoproterenolactivity at a concentration of 10⁷ M. This activity is so low thatapproximately 1% of this maximum activity can be deemed satisfactory.However, activity of at least 10% is preferred, and more particularly15% of said maximum value.

As a function of the curves, it is evident that the mixture of growthfactors according to the invention triggers release of fatty acidsdemonstrating a greater lipolytic activity than that of caffeine,particularly at a far lower concentration.

Examples of compositions with a slimming action containing one or moregrowth factor(s) in combination will now be provided for illustrationwith no limiting nature.

EXAMPLE 1

    ______________________________________                                        m-NTGF                  0.05 g                                                Ozokerite               10.0 g                                                Isopropyl palmitate     10.0 g                                                White Vaseline          15.0 g                                                Preservative            0.2 g                                                 Antioxidants            0.30 g                                                Oily calendula extract  5.0 g                                                 Oily Fucus extract      10.0 g                                                Oily ivy extract        10.0 g                                                Oily arnica extract     5.0 g                                                 Aromatic composition    1.0 g                                                 Vaseline oil qs         100.0 g                                               ______________________________________                                    

EXAMPLE 2

    ______________________________________                                        m-NTGF                   1.00 g                                               Carbopol 940             0.90 g                                               Ethyl alcohol            20.00 g                                              Triethanolamine          0.2 g                                                Glycerin                 5.0 g                                                Fragrance                0.3 g                                                Water-soluble birch extract                                                                            3.0 g                                                Water-soluble ivy extract                                                                              4.0 g                                                Water-soluble algae extract                                                                            4.0 g                                                Water-soluble cola nut extract                                                                         4.0 g                                                Preservative             0.3 g                                                Caffeine                 2.0 g                                                Water qs                 100.0 g                                              ______________________________________                                    

EXAMPLE 3

Slimming O/W Emulsion

    ______________________________________                                        m-NTGF                    20.0 g                                              Volatile silicone 7158    10.0 g                                              Perhydrosqualene          18.0 g                                              Vaseline oil              5.0 g                                               Liquid lanolin            4.0 g                                               Arlacel 165 (Atlas)       6.0 g                                               Tween 60 (Atlas)          2.0 g                                               Cetyl alcohol             1.2 g                                               Stearic acid              2.5 g                                               Triethanolamine           0.1 g                                               Preservative              0.3 g                                               Antioxidants              0.3 g                                               Fat-soluble St. John's-wort extract                                                                     4.0 g                                               Fat-soluble orthosiphon   3.0 g                                               Fat-soluble ivy           4.0 g                                               Fat-soluble arnica        4.0 g                                               Water qs                  100.0 g                                             ______________________________________                                    

EXAMPLE 4

Slimming W/O Emulsion

    ______________________________________                                        EGF                     5.0 g                                                 Protegin X              20.0 g                                                Vaseline oil            10.0 g                                                Glycerin                5.0 g                                                 Magnesium sulfate       0.5 g                                                 Oily calendula extract  5.0 g                                                 Oily sage extract       5.0 g                                                 Oily algae extract      8.0 g                                                 Oily rosemary extract   3.0 g                                                 Aromatic composition    1.0 g                                                 Preservative            0.3 g                                                 Water                   100.0 g                                               ______________________________________                                    

EXAMPLE 5

Slimming O/W Emulsion

    ______________________________________                                        m-NTGF                   0.01 g                                               Caffeine                 1.0 g                                                Propylene glycol         2.0 g                                                PEG 400                  3.0 g                                                Preservative             0.3 g                                                Carbopol 941             0.2 g                                                Isopropyl myristate      1.0 g                                                Cetyl alcohol            3.0 g                                                Stearic acid             3.0 g                                                Glycerol monostearate    3.0 g                                                Corn germ oil            2.0 g                                                Oily arnica extract      5.0 g                                                Butcher's-broom saponins 1.0 g                                                Water-soluble algae extract                                                                            2.0 g                                                Water-soluble ivy extract                                                                              3.0 g                                                Meadowsweet herbasol     3.0 g                                                Fragrance                0.50 g                                               Mineralized water qs     100.0 g                                              ______________________________________                                    

EXAMPLE 6

Slimming O/W Emulsified Gel

    ______________________________________                                        EDGF                     0.5 g                                                Carbopol 940             0.6 g                                                Volatile silicone 7158   3.0 g                                                Purcelin oil             7.0 g                                                Tefose 63                3.0 g                                                Preservative             0.3 g                                                Ethyl alcohol            15.0 g                                               Fragrance                0.4 g                                                Triethanolamine          0.2 g                                                Oily algae extract       6.0 g                                                Oily arnica extract      6.0 g                                                Oily ivy extract         6.0 g                                                Oily rosemary extract    6.0 g                                                Fat-soluble ginseng extract                                                                            4.0 g                                                Alpha-tocopherol nicotinate                                                                            0.05 g                                               Demineralized water qs   100.0 g                                              ______________________________________                                    

EXAMPLE 7

Liposome Slimming Cream

    ______________________________________                                        m-NTGF                   10.0 g                                               Polyglycerolated cetyl alcohol                                                                         3.8 g                                                β-sitosterol        3.8 g                                                Dicetyl phosphate        0.4 g                                                Preservative             0.3 g                                                Sunflower oil            35.0 g                                               Fragrance                0.6 g                                                Carbopol 940             0.2 g                                                Triethanolamine          0.2 g                                                Demineralized water qs   100.0 g                                              ______________________________________                                    

EXAMPLE 8

Orally Administered Treatment Composition

According to the present invention, gel capsules or capsules with thefollowing unit composition are prepared:

    ______________________________________                                        m-NTGF                100.0 mg                                                Aerosol 200           5.0 mg                                                  Zinc stearate         5.0 mg                                                  Talc                  5.0 mg                                                  Lactose qs            400.0 mg                                                ______________________________________                                    

We claim:
 1. A method of treatment for slimming a body part of a personhaving local fat overload, said method comprising: administering to saidperson a slimming effective amount of a composition comprising aneffective amount of at least one growth factor that has lipolyticactivity.
 2. The method of claim 1, wherein said composition istopically administered to said body part.
 3. The method of claim 1,wherein said composition is orally administered to said person.
 4. Themethod of claim 1, wherein said growth factor is selected from the groupconsisting of EGF, FGF, EDGF and m-NTGF.
 5. The method of claim 4,wherein said growth factor is m-NTGF.
 6. The method of claim 1, whereinsaid growth factor is present in said composition in a concentration ofbetween 0.01 and 25 wt. % relative to total weight of the composition.7. The method of claim 6, wherein said growth factor is present in saidcomposition in a concentration of between 0.5 and 10 wt. % relative tototal weight of the composition.
 8. The method of claim 1, wherein saidcomposition is in a form selected from the group consisting of: alotion, an oil-in-water emulsion, a water-in-oil emulsion, a gel, acream, an ointment, an aerosol spray, and a vesicular system.
 9. Themethod of claim 1, wherein said composition comprises at least oneingredient selected from the group consisting of a preservative, afragrance, an oil, an alcohol, a fatty ester and a vitamin.
 10. Themethod of claim 1 wherein said composition further comprises a lipolyticsubstance.
 11. The method of claim 10, wherein said lipolytic substanceis caffeine.
 12. The method of claim 1, wherein said growth factor hasan activity of approximately 1 to 100% of the lipolytic activity ofisoproterenol.
 13. A topical composition for slimming a body part of aperson having local fat overload, said composition comprising:a topicalcarrier, at least one growth factor having a lipolytic activity andcaffeine, said growth factor and said caffeine being present in aslimming effective amount.
 14. The topical composition of claim 13,wherein said growth factor is selected from the group consisting of EGF,FGF, EDGF and m-NTGF.
 15. The topical composition of claim 14, whereinsaid growth factor is m-NTGF.
 16. The topical composition of claim 13,wherein said growth factor is present in a concentration of between 0.01and 25 wt. % relative to total weight of the composition.
 17. Thetopical composition of claim 16, wherein said growth factor is presentin a concentration of between 0.5 and 10 wt. % relative to total weightof the composition.
 18. The topical composition of claim 13, whereinsaid composition is in a form selected from the group consisting of alotion, an oil-in-water emulsion, a water-in-oil emulsion, a gel, acream, an ointment, an aerosol spray, and a vesicular system.
 19. Thetopical composition of claim 13, wherein said composition comprises atleast one ingredient selected from the group consisting of apreservative, a fragrance, an oil, an alcohol, a fatty ester and avitamin.
 20. The topical composition of claim 13, wherein said growthfactor has an activity of approximately 1 to 100% of the lipolyticactivity of isoproterenol.
 21. An oral composition for slimming a bodypart of a person having local fat overload, said compositioncomprising:a oral carrier, at least one growth factor having a lipolyticactivity and caffeine, said growth factor and said caffeine beingpresent in a slimming effective amount.
 22. The composition of claim 21,wherein said growth factor is selected from the group consisting of EGF,FGF, EDGF and m-NTGF.
 23. The composition of claim 21, wherein saidgrowth factor is m-NTGF.
 24. The composition of claim 21, wherein saidgrowth factor is present in a concentration of between 0.01 and 25 wt. %relative to total weight of the composition.
 25. The composition ofclaim 21, wherein said growth factor is present in a concentration ofbetween 0.5 and 10 wt. % relative to total weight of the composition.26. The composition of claim 21, wherein said composition is in a formselected from the group consisting of a lotion, an oil-in-wateremulsion, a water-in-oil emulsion, a gel, a cream, an ointment, anaerosol spray, and a vesicular system.
 27. The composition of claim 21,wherein said composition comprises at least one ingredient selected fromthe group consisting of a preservative, a fragrance, an oil, an alcohol,a fatty ester and a vitamin.
 28. The oral composition of claim 21,wherein said growth factor has an activity of approximately 1 to 100% ofthe lipolytic activity of isoproterenol.
 29. The method of claim 1,wherein said local fat overload comprises cellulitis.
 30. The method ofclaim 13, wherein said local fat overload comprises cellulitis.
 31. Themethod of claim 21, wherein said local fat overload comprisescellulitis.